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Compounds as PDE IV and TNF-inhibitors

a technology of which is applied in the field of compounds as pde iv and inhibitors, can solve the problems of not disclosing or suggesting that the benzamido moiety may be substituted by anything other than methoxy

Inactive Publication Date: 2006-04-20
AVENTIS PHARMA LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Mathison, et al., also do not disclose or suggest that the benzamido moiety may be substituted by anything other than methoxy.
WO Patent Application No. 92 / 12961 also does not disclose compounds wherein a methine moiety of the diether phenyl moiety is substituted by a halomethine moiety or an imine moiety.

Method used

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  • Compounds as PDE IV and TNF-inhibitors
  • Compounds as PDE IV and TNF-inhibitors
  • Compounds as PDE IV and TNF-inhibitors

Examples

Experimental program
Comparison scheme
Effect test

example 1

Compounds A-BH

[0362] A suspension of 3-cyclopentyloxy-6-fluoro-4-methoxybenzoic acid (0.88 g) in dry toluene (10 mL) is treated with thionyl chloride (2 mL) and the mixture is refluxed for 90 minutes. The mixture is cooled and concentrated in vacuo, to give “yellow oil A”.

[0363] A suspension of sodium hydride (0.4 g of a 60% dispersion in mineral oil) in dimethylformamide (5 mL) is treated with a solution of 4-amino-3,5-dichloropyridine (0.82 g) in dimethylformamide (5 mL) and the reaction mixture is stirred at room temperature for 30 minutes. It is then treated with a solution of the “yellow oil A” in dimethylformamide (5 mL) and stirred at 45° C. for 16 hours. It is then cooled, poured into water (50 mL) and extracted with chloroform (3×500 mL). The combined extracts are dried over magnesium sulphate and concentrated. The residual yellow oil is subjected to flash chromatography [a 3:1 mixture of petroleum ether (b.p. 60-80° C.) and ethyl acetate is used as eluent in a silica gel...

example 2

Compounds BI-BJ

[0424] A solution of 4-amino-3,5-dichloropyridine (3.73 g) in dry tetrahydrofuran (50 mL) under nitrogen at 5-10° C. is treated portionwise with sodium hydride (60% dispersion in oil; 1.87 g). After 30 minutes it is treated dropwise with a solution of 3-cyclopent-2-enyloxy-4-methoxybenzoyl chloride in dry tetrahydrofuran (50 mL; that is prepared, as described in Reference Example 6, from 5.89 g 3-cyclopent-2-enyloxy-4-methoxybenzoic acid). The resulting mixture is allowed to warm to room temperature and left to stand overnight. Most of the solvent is then removed under reduced pressure and the residue is partitioned between water (250 mL) and dichloromethane (250 mL) and the aqueous layer is further extracted with dichloromethane (2×250 mL). The combined organic layers are dried over sodium sulfate, the solvent is removed under reduced pressure, and the resulting residue is subjected to flash chromatography on silica gel, eluting with mixtures of ethyl acetate and pe...

example 3

Compounds BK-BL

[0426] A solution of 4-amino-3,5-dichloropyridine (0.93 g) in dry tetrahydrofuran (56 mL) under nitrogen at 5-10° C. is treated portionwise with sodium hydride (60% dispersion in oil, 0.57 g). After 1 hour it is treated dropwise with a solution of 3-cyclopent-3-enyloxy-4-methoxybenzoyl chloride in dry tetrahydrofuran (30 mL) that is prepared as described in Reference Example 7 from 1.33 g 3-cyclopent-3-enyloxy-4-methoxybenzoic acid. The resulting mixture is allowed to warm to room temperature, stirred for a further 3 hours and then poured into 5% aqueous potassium carbonate (430 mL). The resulting emulsion is extracted with ethyl acetate (3×150 mL), the combined organic extracts washed with water (2×20 mL), followed by ice-cold 1 M aqueous hydrochloric acid (2×20 mL) and dried over sodium sulfate. The solvent is removed under reduced pressure and the resulting residue subject to flash chromatography on silica gel, eluting with mixtures of t-butyl methyl ether and cyc...

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Abstract

This invention is directed to a [di(ether or thioether)heteroaryl or fluoro substituted aryl] compound or an N-oxide thereof or a pharmaceutically acceptable salt thereof, which is useful for inhibiting the production or physiological effects of TNF in the treatment of a patient suffering from a disease state associated with a physiologically detrimental excess of tumor necrosis factor (TNF). Compounds within the scope of the present invention also inhibit cyclic AMP phosphodiesterase, and are useful in treating a disease state associated with pathological conditions that are modulated by inhibiting cyclic AMP phosphodiesterase, such disease states including inflammatory and autoimmune diseases, in particular type IV cyclic AMP phosphodiesterase. The present invention is therefore directed to their pharmacological use for inhibiting TNF and / or cyclic AMP phosphodiesterase, pharmacological compositions comprising the compounds and methods for their preparation.

Description

[0001] This is a continuation-in-part of PCT Application Serial No. GB94 / 01630 filed Jul. 28, 1994, that designates the United States, now pending.FIELD OF THE INVENTION [0002] This invention is directed to [di(ether or thioether)heteroaryl or fluoro substituted aryl] compounds, their preparation, pharmaceutical compositions containing these compounds, and their pharmaceutical use in the treatment of disease states associated with proteins that mediate cellular activity. [0003] Disease states associated with abnormally high physiological levels of cytokines such as TNF are treatable according to the invention. TNF is an important pro-inflammatory cytokine which causes hemorrhagic necrosis of tumors and possesses other important biological activities. TNF is released by activated macrophages, activated T-lymphocytes, natural killer cells, mast cells and basophils, fibroblasts, endothelial cells and brain astrocytes among other cells. [0004] The principal in vivo actions of TNF can be...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D401/02C07D413/02C07D213/75C07C255/28C07C237/10C07D239/42A61K31/09A61K31/137A61K31/165A61K31/167A61K31/196A61K31/42A61K31/425A61K31/44A61K31/4402A61K31/4406A61K31/4409A61K31/4412A61K31/4418A61K31/4439A61K31/444A61K31/455A61K31/495A61K31/4965A61K31/50A61K31/501A61K31/505A61K31/53A61P1/04A61P3/10A61P7/12A61P11/00A61P11/06A61P11/08A61P13/12A61P17/00A61P17/02A61P17/04A61P17/06A61P19/02A61P19/08A61P25/00A61P25/28A61P27/16A61P29/00A61P31/00A61P31/04A61P35/02A61P37/06A61P37/08A61P43/00C07C43/225C07C43/247C07C217/58C07C235/56C07C237/30C07C255/60C07C317/14C07C323/20C07C323/65C07C325/02C07C327/42C07C327/48C07D213/50C07D213/61C07D213/65C07D213/66C07D213/69C07D213/70C07D213/80C07D213/81C07D213/82C07D213/89C07D237/14C07D239/46C07D241/18C07D241/20C07D253/06C07D261/14C07D275/02C07D401/12C07D413/12
CPCC07D417/12C07C43/247C07C217/58C07C235/56C07C237/30C07C255/60C07C327/48C07C2101/08C07C2103/64C07C2103/66C07D213/65C07D213/69C07D213/70C07D213/75C07D213/79C07D213/81C07D213/82C07D213/89C07D401/12C07D409/12C07D413/12C07C2601/08C07C2603/64C07C2603/66A61P1/04A61P11/00A61P11/02A61P11/06A61P11/08A61P13/12A61P17/00A61P17/02A61P17/04A61P17/06A61P19/00A61P19/02A61P19/08A61P25/00A61P25/16A61P25/28A61P27/16A61P29/00A61P31/00A61P31/04A61P31/12A61P31/18A61P33/00A61P33/06A61P35/02A61P37/06A61P37/08A61P43/00A61P7/12A61P3/10
Inventor FENTON, GARRYMAJID, TAHIR NADEEMPALFREYMAN, MALCOLM NORMAN
Owner AVENTIS PHARMA LTD
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